Clinical Study on the Therapeutic Effects of Anti-Vascular Endothelial Growth Factor Therapy and Combined Steroid Therapy in Macular Edema Associated with Retinal Vein Occlusion in Relation to Cytokines - Therapeutic Effects of Anti-VEGF Therapy Versus Steroid Combination in RVO
Axonal growth inhibitors and their receptors in spinal cord injury: from biology to clinical translation.
作者: Sílvia Sousa Chambel ; Célia Duarte Cruz
Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelin-associated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19 (that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the RhoA/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.
2023-11-07·European urology oncology
A Phase 2 Trial of Talazoparib and Avelumab in Genomically Defined Metastatic Kidney Cancer.
作者: Ritesh R Kotecha ; Sahil D Doshi ; Andrea Knezevic ; Joshua Chaim ; Yingbei Chen ; Rachel Jacobi ; Mark Zucker ; Ed Reznik ; Deaglan McHugh ; Neil J Shah ; Emily Feld ; David H Aggen ; William Rafelson ; Han Xiao ; Maria I Carlo ; Darren R Feldman ; Chung-Han Lee ; Robert J Motzer ; Martin H Voss
Although different kidney cancers represent a heterogeneous group of malignancies, multiple subtypes including Von Hippel-Lindau (VHL)-altered clear cell renal cell carcinoma (ccRCC), fumarate hydratase (FH)- and succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC), and renal medullary carcinoma (RMC) are affected by genomic instability. Synthetic lethality with poly ADP-ribose polymerase inhibitors (PARPis) has been suggested in preclinical models of these subtypes, and paired PARPis with immune checkpoint blockade (ICB) may achieve additive and/or synergistic effects in patients with previously treated advanced kidney cancers.
To evaluate combined PARPi + ICB in treatment-refractory metastatic kidney cancer.
DESIGN, SETTING, AND PARTICIPANTS:
We conducted a single-center, investigator-initiated phase 2 trial in two genomically selected advanced kidney cancer cohorts: (1) VHL-altered RCC with at least one prior ICB agent and one vascular endothelial growth factor (VEGF) inhibitor, and (2) FH- or SDH-deficient RCC with at least one prior ICB agent or VEGF inhibitor and RMC with at least one prior line of chemotherapy.
Patients received talazoparib 1 mg daily plus avelumab 800 mg intravenously every 14 d in 28-d cycles.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:
The primary endpoint was objective response rate (ORR) by Immune Response Evaluation Criteria in Solid Tumors at 4 mo, and the secondary endpoints included progression-free survival (PFS), overall survival, and safety.
RESULTS AND LIMITATIONS:
Cohort 1 consisted of ten patients with VHL-altered ccRCC. All patients had previously received ICB. The ORR was 0/9 patients; one patient was not evaluable due to missed doses. In this cohort, seven patients achieved stable disease (SD) as the best response. The median PFS was 3.5 mo (95% confidence interval [CI] 1.0, 3.9 mo). Cohort 2 consisted of eight patients; four had FH-deficient RCC, one had SDH-deficient RCC, and three had RMC. In this cohort, six patients had previously received ICB. The ORR was 0/8 patients; two patients achieved SD as the best response and the median PFS was 1.2 mo (95% CI 0.4, 2.9 mo). The most common treatment-related adverse events of all grades were fatigue (61%), anemia (28%), nausea (22%), and headache (22%). There were seven grade 3-4 and no grade 5 events.
The first clinical study of combination PARPi and ICB therapy in advanced kidney cancer did not show clinical benefit in multiple genomically defined metastatic RCC cohorts or RMC.
We conducted a study to look at the effect of two medications, talazoparib and avelumab, in patients with metastatic kidney cancer who had disease progression on standard treatment. Talazoparib blocks the normal activity of molecules called poly ADP-ribose polymerase, which then prevents tumor cells from repairing themselves and growing, while avelumab helps the immune system recognize and kill cancer cells. We found that the combination of these agents was safe but not effective in specific types of kidney cancer.
2023-10-31·Current oncology reports
Management of Central and Peripheral Nervous System Tumors in Patients with Neurofibromatosis.
作者: Rebecca Brown
Neurofibromatosis type I (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis represent a diverse group of genetic tumor predisposition syndromes with a shared feature of tumors affecting the peripheral nerve sheaths. PURPOSE OF REVIEW: Many advancements have been made in understanding the biologic underpinnings of these conditions, and in 2016 the first drug was approved by the FDA to treat pediatric symptomatic unresectable plexiform neurofibromas. RECENT FINDINGS: Mek inhibitors have provided a much-needed therapeutic avenue for NF1 patients with unresectable plexiform neurofibromas (PN), both for reduction of tumor bulk and for improvement in symptoms. Selumetinib is the first FDA approved drug for PN, but is only approved for children. Some research suggests that alternative Mek inhibitors and other mixed tyrosine kinase inhibitors may have better efficacy in adults. Vascular endothelial growth factor (VEGF) inhibitor bevacizumab can prolong hearing and delay the need for surgery in NF2 patients with bilateral vestibular schwannomas. This article provides an update regarding considerations and approaches when treating the tumors associated with the neurofibromatoses (NF), including risk and prognosis metrics, clinical trial results, surgical techniques, and radiation therapy recommendations.
If cells in cell cultures grow while being treated with division-suppressing agents, their growth becomes excessive and they permanently lose their ability to divide. However, if the cells are treated with a combination of division inhibitors and growth inhibitors, they remain capable of dividing after these substances have been discontinued. The findings could be transferred to certain cancer therapies, but first need to be clinically tested and confirmed.
Growth is a fundamental biological process and a prerequisite for living organisms to develop and reproduce. The processes of cell growth (i.e. the production of new biomass) and of cell division must be coordinated with each other.
In multicellular organisms such as humans, the growth of cells must also be coordinated with their environment so that cells are present in the right number and size to form functional tissue or organs. Cell growth is therefore strictly regulated and takes place only when certain growth signals are present.
But cancer cells are different. They grow unchecked, they divide over and over again, and they don't react to stop signals from their environment.
An advantage can be a disadvantage
Now several studies published in the journal Molecular Cell show that uncontrolled growth is not only an advantage for cancer cells but also a weakness.
One of these studies was led by Professor Gabriel Neurohr from the Institute of Biochemistry at ETH Zurich. For several years, he and his group have been researching how cell growth influences cell function. They are also investigating what happens when cells exceed their normal size and enter a state that the researchers refer to as senescence. In this state, the cells are preternaturally large and lose their ability to divide. Nevertheless, they are still active and can influence their environment, such as by releasing messenger substances.
Senescent cells are found in normal tissue and play an important role in the ageing process. However, senescence can also be induced with chemical substances, and because it leads to a loss of the capacity to divide, it is the goal of certain cancer treatments.
A breakdown in DNA repair
Neurohr's colleague Sandhya Manohar has now investigated whether excessive size affects cellular functions in senescent cells. In her research, she treated non-cancerous cell line and a breast cancer cell line with substances that inhibit growth and division.
When she used only division-suppressing substances in her cell cultures, the cells were indeed no longer able to divide, but they continued to grow and went into senescence. As a result, they permanently lost their ability to divide. This effect persisted even after Manohar had discontinued the division inhibitors.
An important reason for the loss of the ability to divide is that the enlarged cells can no longer repair damage to their genetic material, such as double-stranded DNA breaks. Such breaks always occur spontaneously when a cell duplicates its genetic material prior to cell division.
In addition, these cells cannot correctly activate a key signalling pathway (p53-p21), which is critical for a coordinated response to DNA breaks. As a result, the damage is not repaired efficiently enough. What this means for enlarged cells is that numerous irreparable DNA breaks accumulate during division -- to the point where division is no longer possible.
Is combination therapy counterproductive?
Yet when the researchers treated the cells with division-inhibiting and growth-inhibiting substances simultaneously, the cells were able to divide and multiply normally again after both substances were discontinued. "In cancer therapy, this is precisely what you don't want," Neurohr says.
Growth- and division-inhibiting agents are already being used in cancer treatment. "Based on our observations in cell cultures, we would expect an increased relapse rate when treating a tumour with division inhibitors and growth inhibitors at the same time. It would make more sense to first use a division inhibitor, then a drug that further damages the DNA of the cells and makes division completely impossible," Neurohr explains.
Clinical tests needed to confirm findings
Thus far, the ETH researchers have tested their new findings only on cell cultures. With both growth and division strongly dependent on the cell environment, the team cannot transfer these results directly to a clinical setting. Trials with organoids or on tissue samples are thus needed first to better test the potential treatment. Clinical studies investigating various combinations of division inhibitors and other medications are also underway.
The idea put forth by the ETH researchers under Neurohr has support from studies by three other international research teams, also published in the same issue of Molecular Cell.
These studies show that cancer cells with hyperactive growth are sensitive to treatment with division inhibitors. As these substances are already being used to treat certain types of breast cancer, the new findings could have a long-term impact on cancer treatment.
– Results for Exelixis’ next-generation tyrosine kinase inhibitor demonstrated an objective response rate of 38% and a disease control rate of 88% –
– Anti-tumor activity was observed in patients who had progressed on prior VEGFR-tyrosine kinase inhibitors, including cabozantinib –
ALAMEDA, Calif.--(BUSINESS WIRE)-- Exelixis, Inc. (Nasdaq: EXEL) today announced initial results from an expansion cohort of STELLAR-001 evaluating single-agent zanzalintinib in patients with previously treated clear cell renal cell carcinoma (ccRCC). STELLAR-001 is a phase 1b trial evaluating zanzalintinib alone and in combination with atezolizumab in patients with locally advanced or metastatic solid tumors. The findings are being presented today at 2:35 p.m. CST during the Oral Abstracts session at the 2023 International Kidney Cancer Symposium (IKCS): North America.
“Following promising activity in the dose-escalation stage, I am further encouraged by the anti-tumor activity observed in the monotherapy expansion cohort suggesting that zanzalintinib may be an effective therapy following disease progression after prior treatments,” said Sumanta Pal, M.D., Clinical Professor, City of Hope Comprehensive Cancer Center, who is presenting the findings. “Many of these patients with advanced kidney cancer have exhausted their treatment options, having progressed on both immune checkpoint inhibitors and tyrosine kinase inhibitors including cabozantinib, so these results showing strong response rates and durable responses are encouraging for this group of patients.”
In this ccRCC cohort, 97% of patients had received prior immunotherapy and 81% had received prior VEGFR-tyrosine kinase inhibitor (TKI), including 53% who had received cabozantinib. Eighty-one percent of patients were intermediate risk by International Metastatic RCC Database Consortium.
At a median follow-up of 8.3 months, 12 of the 32 patients enrolled in the expansion cohort had a confirmed partial response for an objective response rate of 38%; the disease control rate was 88%. Additional efficacy outcomes by prior therapy subgroups are shown in Table 1.
Patients who received a prior VEGFR-TKI
Any VEGFR-TKI, including cabozantinib (n=26)
Non-cabozantinib VEGFR-TKI (n=8)
Objective response rate, %
Disease control rate, %
Subgroups are not mutually exclusive. Prior cabozantinib exposure was unknown for one patient.
VEGFR-TKI: vascular endothelial growth factor receptor-tyrosine kinase inhibitor.
At data cutoff, 50% of patients were continuing treatment. The median duration of response was 7.4 months for the cabozantinib-naïve group and not estimable for the cabozantinib-exposed group.
“These findings underscore the potential zanzalintinib may hold for patients with refractory kidney cancer, including those who have previously progressed on cabozantinib,” said Amy Peterson, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. “As STELLAR-001 and our phase 3 STELLAR trials progress, we look forward to elucidating the potential of zanzalintinib in kidney cancer as well as in other advanced solid tumors.”
The safety population (n=81) included 32 patients from the ccRCC expansion cohort treated at 100 mg plus 49 patients across different solid tumors from the dose-escalation stage who received single-agent zanzalintinib at doses ranging from 10-140 mg. The safety pro similar between the ccRCC cohort and the safety population. Discontinuations due to treatment-related adverse events (AEs) occurred in 9% of patients in the ccRCC cohort and 12% of patients in the safety population. There were three grade 5 treatment-emergent AEs in the ccRCC cohort and two more in the safety population; none were treatment-related, nor was the single grade 4 event. Of note, the rate of palmar plantar erythrodysesthesia was low with zanzalintinib (9% in the ccRCC cohort and 12% in the safety population, all grade 1-2).
STELLAR-001 (NCT03845166) is a global, open-label phase 1b/2 study of zanzalintinib as a single agent or in combination with atezolizumab in patients with inoperable locally advanced or metastatic solid tumors. The trial is divided into two parts: a dose-escalation stage and an expansion cohort stage. The expansion cohorts evaluating zanzalintinib as a single agent or in combination with atezolizumab include patients with: ccRCC, non-clear cell RCC, breast cancer that is hormone receptor-positive and HER-2 negative, castration-resistant prostate cancer and colorectal cancer. More information about the trial is available at ClinicalTrials.gov.
Zanzalintinib is a next-generation oral TKI that inhibits the activity of receptor tyrosine kinases implicated in cancer growth and spread, including VEGF receptors, MET, AXL and MER. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis and resistance to multiple therapies, including immune checkpoint inhibitors. With zanzalintinib, Exelixis sought to build upon its extensive experience with the target pro cabozantinib, the company’s flagship medicine, while improving key characteristics, including pharmacokinetic half-life. Zanzalintinib is currently being developed for the treatment of advanced solid tumors, including genitourinary, colorectal and head and neck cancers.
Zanzalintinib is not approved for ccRCC.
Kidney cancer is among the top 10 most commonly diagnosed forms of cancer among both men and women in the U.S.1 An estimated 81,800 Americans will be diagnosed with kidney cancer in 2023.1 The most common type of kidney cancer in adults is ccRCC.2 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 15%.3 In 2022, approximately 32,200 patients with advanced kidney cancer required systemic therapy in the U.S., with over 20,000 patients receiving first-line treatment.4
About CABOMETYX® (cabozantinib)
In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib; for patients with advanced RCC as a first-line treatment in combination with nivolumab; and for adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen Pharma SAS exclusive rights for the commercialization and further clinical development of cabozantinib outside of the U.S. and Japan. In 2017, Exelixis granted exclusive rights to Takeda for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the U.S.
CABOMETYX IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.
Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.
Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose.
Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.
Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.
Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.
With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and resume at a reduced dose based on severity.
Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.
Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.
Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.
Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria; resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.
Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose.
Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients.
Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.
Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.
In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.
Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.
Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.
The most common (≥20%) adverse reactions are:
CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, and constipation.
CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.
Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.
Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.
USE IN SPECIFIC POPULATIONS
Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.
Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.
Please see accompanying full Prescribing Information .
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit or call 1-800-FDA-1088.
Exelixis is a globally ambitious oncology company innovating next-generation medicines and regimens at the forefront of cancer care. Powered by bi-coastal centers of discovery and development excellence, we are rapidly evolving our product portfolio to target an expanding range of tumor types and indications with our clinically differentiated pipeline of small molecules, antibody-drug conjugates and other biotherapeutics. This comprehensive approach harnesses decades of robust investment in our science and partnerships to advance our investigational programs and extend the impact of our flagship commercial product, CABOMETYX® (cabozantinib). Exelixis is driven by a bold scientific pursuit to create transformational treatments that give more patients hope for the future. For information about the company and its mission to help cancer patients recover stronger and live longer, visit , follow @ExelixisInc on X (Twitter), like Exelixis, Inc. on Facebook and follow Exelixis on LinkedIn.
This press release contains forward-looking statements, including, without limitation, statements related to: Exelixis’ presentation of data from STELLAR-001 during the Oral Abstracts session at the 2023 IKCS: North America; the therapeutic potential of zanzalintinib to treat patients with refractory ccRCC, including those who have previously progressed on cabozantinib; Exelixis’ plans to continue studying the therapeutic potential of zanzalintinib in kidney cancer as well as in other advanced solid tumors; and Exelixis’ scientific pursuit to create transformational treatments that give more patients hope for the future. Any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements and are based upon Exelixis’ current plans, assumptions, beliefs, expectations, estimates and projections. Forward-looking statements involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of these risks and uncertainties, which include, without limitation: the availability of data at the referenced times; complexities and the unpredictability of the regulatory review and approval processes in the U.S. and elsewhere; Exelixis’ continuing compliance with applicable legal and regulatory requirements; the potential failure of zanzalintinib, both alone and in combination with other therapies, to demonstrate safety and/or efficacy in future clinical testing; uncertainties inherent in the product development process; the costs of conducting clinical trials; Exelixis’ dependence on third-party vendors for the development, manufacture and supply of zanzalintinib; Exelixis’ ability to protect its intellectual property rights; market competition; changes in economic and business conditions; and other factors affecting Exelixis and its development programs detailed from time to time under the caption “Risk Factors” in Exelixis’ most recent Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q, and in Exelixis’ future filings with the Securities and Exchange Commission. All forward-looking statements in this press release are based on information available to Exelixis as of the date of this press release, and Exelixis undertakes no obligation to update or revise any forward-looking statements contained herein, except as required by law.
Exelixis, the Exelixis logo and CABOMETYX are registered U.S. trademarks of Exelixis.
1 Key Statistics About Kidney Cancer. American Cancer Society website. Available at: . Accessed November 2023.
2 What Is Kidney Cancer? American Cancer Society website. Available at . Accessed November 2023.
3 Survival Rates for Kidney Cancer. American Cancer Society website. Available at . Accessed November 2023.
4 Citeline’s Datamonitor Healthcare: Renal Cell Carcinoma. March 2023 (internal data on